Microglia and Synaptic Plasticity: Uncovering Hibernation Mechanisms to Combat Neurodegeneration

Dementia ranks as the seventh leading cause of global mortality, with its prevalence on the rise due to aging demographics, population growth, and the lack of curative therapies. Alzheimer’s disease and related neurodegenerative conditions, collectively known as ‘tauopathies’, are characterized by abnormal accumulations of hyperphosphorylated Tau protein and synaptic dysfunction, correlating strongly with cognitive decline. Intriguingly, hibernating animals undergo physiological Tau hyperphosphorylation and synapse loss resembling early Alzheimer's stages. Entrance into torpor triggers Tau phosphorylation akin to patterns seen in Alzheimer’s disease, accompanied by significant synapse loss. Remarkably, upon arousal, these processes reverse, leading to Tau dephosphorylation and synapse restoration. Given the parallels between hibernation and early-stage tau-induced disease, we hypothesize shared mechanisms driving synaptic remodeling. Thus, this project delves into the common pathways between hibernation and tauopathy-induced synaptic remodeling. Our goal is to unveil shared synaptic degeneration pathways and identify hibernation-specific mechanisms for synaptic recovery. By profiling hippocampal synaptosome interactomes across hibernation stages, we aim to uncover protein-protein interactions implicated in synapse loss and regeneration. Subsequently, we will evaluate the conservation of these interactions across various tauopathy models.